The prostate gland harbors many types of premalignant lesions (such as prostatic intraepithelial neoplasia: PIN, atypical adenomatous hyperplasia, AAH), but not all of them progress to prostate cancer (PC). When high-grade PIN (HGPIN) is found in a biopsy section, the pathologist suspects PC and the patient becomes a candidate for a repeat biopsy. The question arises: Which HGPINs are precursors to PC and which are not? Who should be biopsied repeatedly and who should not? Our central hypothesis is that cathepsin B (CB) and stefin A, and van Wildebrand factor VIII (vWF) are molecular markers that can distinguish HGPINs with the potential of progressing to PC from those that would not. We further hypothesize that immediate precursor HGPIN should be linked to a CB>stefin A ratio, increased microvessel density, wide spread degradation of basement membrane (BM) and local invasion of basal cells. Whereas, distant predecessor HGPIN and low-grade PIN (LGPIN) should be linked to CB<stefin A and/or CB=stefin A and decreased microvessel density. Our rationale is that, once biomarkers are linked to PIN types, they could be used in selecting patients for repeat biopsy. We will test our hypothesis using the Specific Aims: Aim 1: (a) Characterize the immediate precursor and distant predecessor HGPINs associated with PC in biopsy and/or transurethral resection of prostate (TURP) and prostatectomy samples of white and African American men. (b) Determine CB and stefin A proteins in laser capture (LCM) microdissected HGPINs by Elisa assay. Aim 2: Determine mierovessel density associated with HGPIN by quantitative image analysis of localized vWF. Identification of immediate precursor HGPIN to PC may lead to approaches for delaying or even preventing development of frank malignancy, thereby decreasing death due to this cancer. Our research is significant because the molecular marker criteria will aid selecting which patient with HGPIN in the initial biopsy/TURP will need repeat biopsy and thus, sparing those patients who do not from the associated trauma and pain and thus, reducing cost.